rs200476861

chr5-156344577-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BS1_Supporting

The NM_000337.6(SGCD):c.92G>A(p.Arg31Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,612,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SGCD NM_000337.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:1
• Conservation: PhyloP100: 9.86

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

LOC124901120 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152018) while in subpopulation NFE AF= 0.000309 (21/67996). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCD	NM_000337.6	c.92G>A	p.Arg31Gln	missense_variant	3/9	ENST00000337851.9
LOC124901120	XR_007059016.1	n.234+2876C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000337851.9	c.92G>A	p.Arg31Gln	missense_variant	3/9	1	NM_000337.6	P4
SGCD	ENST00000435422.7	c.89G>A	p.Arg30Gln	missense_variant	2/8	1		A1
SGCD	ENST00000517913.5	c.92G>A	p.Arg31Gln	missense_variant	5/10	5
SGCD	ENST00000524347.2	c.92G>A	p.Arg31Gln	missense_variant, NMD_transcript_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000174 AC: 43 AN: 247440 Hom.: 0 AF XY: 0.000186 AC XY: 25 AN XY: 134316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000289 AC: 422 AN: 1460006 Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 197 AN XY: 726238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74242

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000182 AC: 22

EpiCase AF: 0.000546

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30564623, Pourebrahim2021[article], 33919104) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2F Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 31 of the SGCD protein (p.Arg31Gln). This variant is present in population databases (rs200476861, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 196255). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 11, 2018	The p.Arg31Gln variant in SGCD has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 0.03% (39/126184) of European chr omosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.Arg31Gln variant is uncertain. ACM G/AMP Criteria applied: BS1_Supporting, PP3. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2023	Variant summary: SGCD c.92G>A (p.Arg31Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 247440 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.92G>A has been reported in the literature in individuals affected with dilated cardiomyopathy or sudden cardiac death with left ventricular hypertrophy without evidence of cosegregation with disease (Pourebrahim_2021, Iglesias_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33919104, 34790974). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Qualitative or quantitative defects of delta-sarcoglycan Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 05, 2019

- -

Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 03, 2021

- -

Dilated cardiomyopathy 1L Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MVP		0.89
MPC		0.62
ClinPred		0.64	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200476861; hg19: chr5-155771587; COSMIC: COSV61907410;